Background
Methods
Patients
Open run-in, randomization and masking
Outcome measures
Statistical analysis
Results
Study population
Outcome after open run-in phase (all patients)
Screening1) | End of run-in1) | Change from screening to end of run-in2) | ||||
---|---|---|---|---|---|---|
Dose level after run-in | ||||||
maximum dose | – | – | 76% | 29/38 | – | – |
step 3 dose | – | – | 18% | 7/38 | – | – |
step 2 dose | – | – | 5% | 2/38 | – | – |
Systolic blood pressure [mmHg] | 111 ± 13 | n = 41 | 102 ± 14 | n = 38 | −9 [−13 to −5]* | n = 37 |
Echocardiography | ||||||
Left ventricle fractional shortening [%] | 35 ± 3 | n = 42 | 36 ± 4 | n = 38 | 0 [−1 to 2] | n = 38 |
Electrocardiogram (ECG) | ||||||
Ventricular heart rate [beats/min] | 97 ± 14 | n = 41 | 88 ± 16 | n = 38 | −9 [−13 to −4]* | n = 37 |
Holter-Electrocardiogram (Holter-ECG) | ||||||
Ventricular heart rate [beats/min]: | ||||||
minimum | 73 ± 10 | n = 38 | 69 ± 11 | n = 35 | −2 [−6 to 2] | n = 34 |
maximum | 140 ± 15 | n = 38 | 129 ± 15 | n = 35 | −11 [−16 to −6]* | n = 34 |
mean | 101 ± 13 | n = 38 | 93 ± 11 | n = 35 | −8 [−13 to −3]* | n = 34 |
Heart rate variability (Holter ECG) | ||||||
mean NN [ms] | 574 ± 122 | n = 23 | 627 ± 140 | n = 21 | 52 [24 to 81]* | n = 19 |
SDNN [ms] | 85 ± 23 | n = 22 | 97 ± 29 | n = 21 | 12 [3 to 21]* | n = 19 |
SDANN [ms] | 69 ± 24 | n = 23 | 73 ± 24 | n = 21 | 0 [−12 to 13] | n = 20 |
ASDNN [ms] | 45 ± 18 | n = 22 | 57 ± 21 | n = 21 | 11 [5 to 18]* | n = 19 |
rMSSD [ms] | 35 ± 18 | n = 24 | 46 ± 23 | n = 22 | 9 [−1 to 18] | n = 21 |
pNN50 [%] | 9 ± 8 | n = 24 | 15 ± 13 | n = 21 | 5 [1 to 10]* | n = 20 |
Preferred term | No. | % | 95% confidence intervals |
---|---|---|---|
Total number of patients | 41 | 100%; | |
Patients with at least one AE | 37 | 90% | (77–97%) |
Headache | 11 | 27% | (14–43%) |
Nasopharyngitis | 11 | 27% | (14–43%) |
Cough | 8 | 20% | (9–35%) |
Nausea | 8 | 20% | (9–35%) |
Febrile infection | 6 | 15% | (6–29%) |
Diarrhoea | 5 | 12% | (4–26%) |
Dizziness | 4 | 10% | (3–23%) |
Fall | 3 | 7% | (2–20%) |
Fatigue | 3 | 7% | (2–20%) |
Pyrexia | 3 | 7% | (2–20%) |
Abdominal pain | 2 | 5% | (0.6–17%) |
Back pain | 2 | 5% | (0.6–17%) |
Chest pain | 2 | 5% | (0.6–17%) |
Decreased appetite | 2 | 5% | (0.6–17%) |
Muscular weakness | 2 | 5% | (0.6–17%) |
Rash | 2 | 5% | (0.6–17%) |
Baseline measurements before randomization
Enalapril and Metoprolol 1) | Placebo 1) | |||
---|---|---|---|---|
Age [years] | 12 ± 1.2 | n = 21 | 11 ± 1.1 | n = 17 |
Body Mass Index [kg/m2] | 23 ± 6 | n = 20 | 21 ± 5 | n = 17 |
Ability to rise from supine position | 24% | 5/21 | 24% | 4/17 |
Preserved ability to walk | 33% | 7/21 | 41% | 5/17 |
Maximum walking distance [m] | 200 (3–6000)2) | n = 7 | 300 (30–800)2) | n = 5 |
Systolic blood pressure [mmHg] | 103 ± 16 | n = 21 | 101 ± 11 | n = 17 |
Patients with presence of cardiac symptoms | 0% | 0/21 | 0% | 0/17 |
Steroid use or history of steroid use | 76% | 16/21 | 59% | 10/17 |
NYHA class | ||||
Not applicable | 52% | 11/21 | 59% | 10/17 |
NYHA class I | 48% | 10/21 | 35% | 6/17 |
NYHA class II | 0% | 0/21 | 6% | 1/17 |
Quality of life (KINDL total score at screening) | 70.8 ± 10.1 | n = 21 | 75.6 ± 10.0 | n = 17 |
Echocardiography | n = 21 | n = 17 | ||
Left ventricle fractional shortening [%] | 35 ± 3 | 36 ± 4 | ||
Electrocardiogram (ECG) | n = 21 | n = 17 | ||
Ventricular heart rate [beats/min] | 84 ± 14 | 94 ± 16 | ||
Holter-Electrocardiogram (Holter-ECG) | n = 20 | n = 15 | ||
Ventricular heart rate [beats/min] | ||||
minimum | 67 ± 12 | 72 ± 10 | ||
maximum | 126 ± 17 | 133 ± 11 | ||
mean | 90 ± 12 | 97 ± 9 | ||
Heart rate variability (Holter ECG) | n = 11 | n = 10 | ||
Mean NN [ms] | 678 ± 80 | 571 ± 174 | ||
SDNN [ms] | 98 ± 29 | 96 ± 30 | ||
SDANN [ms] | 71 ± 24 | 75 ± 25 | ||
ASDNN [ms] | 60 ± 20 | 54 ± 21 | ||
rMSSD [ms] | 46 ± 26 | 45 ± 21 | ||
pNN50 [%] | 17 ± 15 | 13 ± 11 |
Outcome after randomization
Results-efficacy-primary
Results-efficacy-secondary
Enalapril and Metoprolol | Placebo | Adjusted Difference 1) | ||||
---|---|---|---|---|---|---|
Systolic blood pressure [mmHg] | 104 ± 13 | n = 19 | 108 ± 14 | n = 14 | −2.5 [−10.9 to 5.9] | n = 38 |
Echocardiography | ||||||
Left ventricle fractional shortening [%] | 34 ± 3.9 | n = 19 | 33 ± 5.7 | n = 15 | 0.6 [−2.0 to 3.2] | n = 38 |
Left ventricle diastolic diameter [cm] | 4 ± 0.5 | n = 19 | 4 ± 0.4 | n = 15 | 0.1 [−0.2 to 0.4] | n = 38 |
Interventricular septum systolic thickness [cm] | 1 ± 0.2 | n = 12 | 1 ± 0.5 | n = 8 | −0.1 [−1.5 to 1.3] | n = 18 |
Electrocardiogram (ECG) | ||||||
Ventricular heart rate [beats/min] | 84 ± 16 | n = 18 | 96 ± 12 | n = 15 | −4.8 [−12.5 to 2.9] | n = 38 |
P-wave [ms] | 84 ± 14 | n = 18 | 73 ± 14 | n = 15 | 10.3 [2.1 to 18.6]* | n = 38 |
PQ-interval [ms] | 129 ± 20 | n = 18 | 115 ± 12 | n = 15 | 10.9 [2.1 to 19.7]* | n = 38 |
QRS-time [ms] | 102 ± 67 | n = 18 | 86 ± 9 | n = 15 | 5.5 [−2.4 to 13.3] | n = 38 |
QTc-time [ms] | 405 ± 28 | n = 18 | 415 ± 33 | n = 15 | −9.2 [−26.4 to 8.0] | n = 38 |
Holter-Electrocardiogram (Holter-ECG) | ||||||
Ventricular heart rate [beats/min]: | ||||||
Minimum | 68 ± 12 | n = 15 | 75 ± 12 | n = 14 | −2.6 [−10.5 to 5.3] | n = 32 |
Maximum | 123 ± 14 | n = 15 | 136 ± 15 | n = 14 | −16.7[−25.6 to −7.9]* | n = 32 |
Mean | 91 ± 13 | n = 15 | 101 ± 14 | n = 14 | −5.2 [−12.8 to 2.3] | n = 32 |
Heart rate variability (Holter ECG) | ||||||
mean NN [ms] | 681 ± 86 | n = 8 | 650 ± 82 | n = 6 | −54.1 [− 160.2 to 52.0] | n = 17 |
SDNN [ms] | 85 ± 31 | n = 9 | 90 ± 46 | n = 7 | −17.8 [−52.4 to 16.9] | n = 18 |
SDANN [ms] | 59 ± 29 | n = 9 | 66 ± 36 | n = 7 | −19.0 [−47.4 to 9.4] | n = 18 |
ASDNN [ms] | 52 ± 18 | n = 9 | 55 ± 33 | n = 7 | −13.0 [−37.5 to 11.6] | n = 18 |
rMSSD [ms] | 37 ± 15 | n = 9 | 41 ± 32 | n = 7 | −12.9 [−40.2 to 14.3] | n = 19 |
pNN50 [%] | 12 ± 9 | n = 9 | 13 ± 14 | n = 7 | −6.8 [−20.3 to 6.7] | n = 18 |
Quality of life (KINDL total score) 2) | 74.7 ± 12.3 | n = 15 | 76.4 ± 6.4 | n = 14 | 1.5 [−4.3 to 7.4] | n = 36 |
Biomarker and neurohumoral markers 3) | ||||||
NT-proBNP [pg/ml] | 90 ± 69 | n = 16 | 52 ± 42 | n = 13 | 12 [− 13 to 38] | n = 28 |
Noradrenalin [pg/ml] | 355 ± 139 | n = 12 | 188 ± 58 | n = 9 | 124 [21 to 228]* | n = 17 |
Renin [pg/ml] | 297 ± 357 | n = 16 | 38 ± 43 | n = 12 | 332 [119 to 545]* | n = 27 |
Aldosteron [ng/ml] | 0.077 ± 0.097 | n = 13 | 0.056 ± 0.036 | n = 11 | 0.032 [−0.027 to 0.090] | n = 24 |
Angiotensin II [pmol/ml] | 19.4 ± 32.4 | n = 16 | 15.6 ± 13.8 | n = 12 | −6.1 [−31.3 to 19.1] | n = 27 |
Results-safety/tolerability
Enalapril and Metoprolol | Placebo | Difference between groups | ||||
---|---|---|---|---|---|---|
Preferred term | No. | (%) | No. | (%) | (%) | 95% confidence intervals |
Total number of patients | 21 | (100%) | 16 | (100%) | ||
Patients with at least one AE | 21 | (100%) | 15 | (94%) | 6% | (−10 to 28%) |
Febrile infection | 11 | (52%) | 5 | (31%) | 21% | (−10 to 47%) |
Nasopharyngitis | 10 | (48%) | 5 | (31%) | 16% | (−15 to 43%) |
Diarrhoea | 6 | (29%) | 1 | (6%) | 22% | (−4 to 44%) |
Cough | 4 | (19%) | 5 | (31%) | −12% | (−39 to 15%) |
Headache | 4 | (19%) | 5 | (31%) | −12% | (− 39 to 15%) |
Mechanical ventilation | 3 | (14%) | 1 | (6%) | 8% | (−16 to 29%) |
Abdominal pain upper | 3 | (14%) | 0 | 14% | (−7 to 35%) | |
Gastroenteritis | 3 | (14%) | 0 | 14% | (−7 to 35%) | |
Spinal operation | 2 | (10%) | 3 | (19%) | −9% | (−34 to 14%) |
Immunisation | 2 | (10%) | 2 | (13%) | −3% | (−27 to 18%) |
Pyrexia | 2 | (10%) | 2 | (13%) | −3% | (−27 to 18%) |
Lower limb fracture | 2 | (10%) | 1 | (6%) | 3% | (−20 to 23%) |
Oropharyngeal pain | 2 | (10%) | 1 | (6%) | 3% | (−20 to 23%) |
Chest pain | 2 | (10%) | 0 | 10% | (−11 to 29%) | |
Fatigue | 2 | (10%) | 0 | 10% | (−11 to 29%) | |
Humerus fracture | 2 | (10%) | 0 | 10% | (−11 to 29%) | |
Influenza like illness | 2 | (10%) | 0 | 10% | (−11 to 29%) | |
Photosensitivity reaction | 2 | (10%) | 0 | 10% | (− 11 to 29%) | |
Tonsillitis | 2 | (10%) | 0 | 10% | (−11 to 29%) | |
Upper respiratory tract infection | 2 | (10%) | 0 | 10% | (−11 to 29%) |
Discussion
Conclusions
Acknowledgements
-
Julia Halbfass, Department Pediatric Cardiology, Erlangen University Hospital, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
-
Jasmin Webinger, Department Pediatric Cardiology, Erlangen University Hospital, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
-
Anja Weise, Department Pediatric Cardiology, Erlangen University Hospital, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
-
Franz Herrndobler, Department Pediatric Cardiology, Erlangen University Hospital, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
-
Mateja Nerad, Department Pediatric Cardiology, Erlangen University Hospital, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
-
Amira Shabaiek, Department Pediatric Cardiology, Erlangen University Hospital, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
-
Güler Akin-Erdinc, Department Pediatric Cardiology, Erlangen University Hospital, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
-
Verena Greim, Department Pediatric Cardiology, Erlangen University Hospital, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
-
Dorothée Böcker, Department Pediatric Cardiology, Erlangen University Hospital, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
-
Stefanie Siepe, Clinical Trials Unit of the Medical Center, University of Freiburg, Freiburg, Germany
-
Sabine Schneider-Fuchs, Clinical Trials Unit of the Medical Center, University of Freiburg, Freiburg, Germany
-
Brigitte Egenhofer-Kummert, Clinical Trials Unit of the Medical Center, University of Freiburg, Freiburg, Germany
-
Barbara Burkhardt, University Heart Center Freiburg-Bad Krozingen, Department of Congenital Heart Disease and Pediatric Cardiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
-
Elena Neumann, Department of Congenital Heart Defects and Pediatric Cardiology, Heart Centre, University of Freiburg, Freiburg, Germany
-
Rudolf Korinthenberg, Department of Neuropediatrics and Muscle Disorders, Medical Center, University of Freiburg, Freiburg, Germany
-
Christian Apitz, Pediatric Heart Center, University Hospital UKGM, Justus-Liebig University, Division of Pediatric Heart Surgery, Giessen, Germany
-
Matthias Freund, Department of Paediatric Cardiology, Elisabeth Children’s Hospital, Oldenburg, Germany
-
Michael Schumacher, Department of Paediatric Cardiology, Elisabeth Children’s Hospital, Oldenburg, Germany
-
Verena Gravenhorst, Department of Paediatric Cardiology and Intensive Care Medicine, Heart Center, University Medical Center Göttingen, Göttingen, Germany
-
Daniela Deppe, Department of Paediatric Cardiology, University Medical Center Göttingen, Göttingen, Germany
-
Joachim Eichhorn, Department of Paediatric Cardiology, University of Heidelberg, Heidelberg, Germany